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PLoS One. 2014 Feb 4;9(2):e87923. doi: 10.1371/journal.pone.0087923. eCollection 2014.

A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease.

Author information

1
BioFocus, Saffron Walden, United Kingdom.
2
BioFocus, Leiden, Netherlands.
3
Galapagos, Leiden, Netherlands.
4
CHDI Management/CHDI Foundation, Princeton, New Jersey, United States of America ; CHDI Management/CHDI Foundation, Los Angeles, California, United States of America.

Abstract

Huntington's disease (HD) is a devastating, genetic neurodegenerative disease caused by a tri-nucleotide expansion in exon 1 of the huntingtin gene. HD is clinically characterized by chorea, emotional and psychiatric disturbances and cognitive deficits with later symptoms including rigidity and dementia. Pathologically, the cortico-striatal pathway is severely dysfunctional as reflected by striatal and cortical atrophy in late-stage disease. Brain-derived neurotrophic factor (BDNF) is a neuroprotective, secreted protein that binds with high affinity to the extracellular domain of the tropomyosin-receptor kinase B (TrkB) receptor promoting neuronal cell survival by activating the receptor and down-stream signaling proteins. Reduced cortical BDNF production and transport to the striatum have been implicated in HD pathogenesis; the ability to enhance TrkB signaling using a BDNF mimetic might be beneficial in disease progression, so we explored this as a therapeutic strategy for HD. Using recombinant and native assay formats, we report here the evaluation of TrkB antibodies and a panel of reported small molecule TrkB agonists, and identify the best candidate, from those tested, for in vivo proof of concept studies in transgenic HD models.

PMID:
24503862
PMCID:
PMC3913682
DOI:
10.1371/journal.pone.0087923
[Indexed for MEDLINE]
Free PMC Article

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